Transforming growth factor-beta (TGF-β) is a prototype for a large family of growth and differentiation factors that regulate development. TGF-β family members activate transmembrane serine/threonine receptor kinases, thereby initiating a signaling cascade via Smads, a novel class of intracellular signaling effectors that regulate gene expression. TGF-β is a potent inducer of growth arrest in many cell types, including epithelial cells. This activity is the basis of the tumor suppressor role of the TGF-β signaling system in carcinomas. Other activities, including TGF-β-induced epithelial-to-mesenchymal differentiation, contribute to cancer progression. TGF-β family signaling is of special relevance in mesenchymal differentiation, including bone development. Deregulated expression or activation of components of this signaling system can contribute to skeletal diseases, e.g. osteoarthritis. See Wakefield, et al. (2002) Current Opinion in Genetics & Development 12:22-29; Siegel, et al. (2003) Nature Reviews (Cancer) 3:807-820; Dumont, et al. (2003) Cancer Cell 3:531-536.
A number of compounds (for example WO 02/094833, WO 04/048382, WO 04/048381, WO 04/050659, WO 04/021989, WO 04/026871, WO 04/026307) have been identified as TGF-β inhibitors. However, there still remains a need for treatment in this field for compounds that are capable of inhibiting TGF-β signaling.
The present invention provides new inhibitors of TGF-β signaling useful for the treatment of conditions resulting from enhanced TGF-β activity or overproduction.